There has been a significant and sustained growth in new drug production featuring monoclonal antibodies and other proteins, approximately 15-20% annually. This growth is due to expanding drug pipelines, as well as more efficient cell lines and bioreactor growth optimizations. The annual bio-production costs are currently estimated at $2.6 billion. One of the most significant investments a drug manufacturer has to make is process chromatography (approximately 30% or $850 million annually).
Chromatography is an integral part of drug production; its purpose in the biotechnology industry is to purify the product proteins from contaminating species. The industry has started to recognize that the efficiency of the chromatography steps which are used to purify the product proteins are no longer keeping up with production demands. There are multiple reasons for this.
First, no significant improvements have been made to the column chromatography process in the past 30 years; most of the work in the industry has been focused on new resin development. A notable exception is membrane chromatography which was recently adopted by the industry.
Second, upstream technology has improved tremendously in the same time period—the bioreactors are larger (up to 20,000 liters), and the titers are much higher (up to 15 g/L compared with 1-2 g/L five years ago). As a result of longer fermentation times, there are generally more impurities in the bioreactor effluent solution. All of the above reasons result in a much heavier load for the downstream purification.
Third, column chromatography has inherent physical limitations. Columns larger than 2 meters in diameter do not scale up. The largest columns in the market are 2 meter diameter and 40 cm bed height. They fit 1,250 L of resin. Assuming a binding capacity of 30 g/L of resin (common Protein A resin capacity for monoclonal antibodies), a single cycle can bind 38 kg. A 20,000 L bioreactor with an output of 10 g/L would produce a load of 200 kg. This means that the biggest column in the market would have to run at least 6 full cycles to process a single batch. The operation can take up to 24 hrs and can result in a significant bottleneck for the manufacturing process.
Finally, in the present marketplace, disposability in the manufacturing process is gaining popularity. Disposable process steps save labor, do not require cleaning validation and are easier to run for the manufacturing personnel. Strides have been made in most downstream processes to have disposable systems. These include bioreactors (up to 2,000 L from Xcellerex Corp.), microfiltration (KleenPak TFF technology from Pall Corp.), depth filtration (POD from Millipore Corp.), sterile filtration (all major manufacturers), tangential flow filtration (all major manufacturers) and membrane chromatography (Mustang, Pall Corp., Sartobind, and Sartorius Corp.). In the past three years, disposable pre-packed chromatography columns have been brought to market by Repligen (OPUS) and W.R. Grace (ProVance). These products may provide ease of use and speed in clinical manufacturing, but are generally considered to be too expensive to use in commercial and large scale manufacturing due to the inherent limitations of the column format.
U.S. Pat. Nos. 7,947,175 and 7,988,859 to Oleg Shinkazh, entitled, “Continuous Countercurrent Tangential Chromatography” and “Countercurrent Tangential Chromatography Methods, Systems and Apparatus”, respectively, disclose methods, systems and apparatus for a new technique of continuous countercurrent tangential chromatography, which address some of the challenges of the prior art. U.S. Pat. Nos. 7,947,175 and 7,988,859 are incorporated herein in their entirety as if fully restated. However, a method, system, and apparatus of tangential chromatography using countercurrent flow including improvements in pressure profile, economics, productivity, robustness and reduced complexity would be desirable in the art.